Version May 2024
INTRODUCTION — Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum and spreads extensively within the confines of the abdominal cavity. Morbidity and mortality are almost entirely due to disease progression within the peritoneum and not distant metastatic spread.
This topic review will cover the treatment of MPM. The epidemiology, histology, clinical features, diagnosis, and staging of MPM, as well as the treatment of pleural, pericardial, and tunica vaginalis mesothelioma are presented elsewhere. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging" and "Epidemiology of malignant pleural mesothelioma" and "Presentation, initial evaluation, and prognosis of malignant pleural mesothelioma" and "Initial management of malignant pleural mesothelioma" and "Systemic treatment for unresectable malignant pleural mesothelioma".)
DIFFUSE MALIGNANT PERITONEAL MESOTHELIOMA
General treatment principles and historic evolution — There is no consensus as to the optimal treatment for MPM. Due to the rarity of this entity, most of the available clinical information about treatment has been derived from retrospective single-center series, which have inherent selection biases. Prospective clinical trials are few and small, and there are currently no randomized studies that compare one treatment with another. Much of the data on systemic therapy in MPM are derived from pharmaceutical company Expanded Access Programs, which have more heterogeneous patient populations and less rigorous response assessment and toxicity reporting than a prospective clinical trial. Determinations about the activity of systemic anticancer agents are often extrapolated from the more extensive data available from patients with pleural mesothelioma. (See "Systemic treatment for unresectable malignant pleural mesothelioma".)
Compounding the difficulty of interpreting data from select small series, MPM is quite heterogeneous in clinical behavior (particularly between men and women) [1,2]. There are many prognostic variables, some of which are only assessable at surgical evaluation. The different histologic types have different natural histories; the sarcomatoid or biphasic subtype has a worse prognosis than the more common epithelial subtype [3,4], and there are two variants, both of which arise predominantly in women, that are associated with indolent clinical behavior. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Histology' and 'Peritoneal mesothelioma variants' below.)
The following sections will focus on diffuse MPM, the most common clinical presentation. Management of the well-differentiated papillary and multicystic variants is described below. (See 'Peritoneal mesothelioma variants' below.)
Conventional therapy — Diffuse MPM was originally treated with a combination of systemic chemotherapy, palliative surgery, and whole abdominal irradiation [5]. The regimen was exceedingly toxic; median survival was less than one year, and long-term survival was uncommon [5-7]. The median survival for untreated patients is approximately six months [2]. An overview of selected historical series of MPM treated with conventional therapies is provided in the table (table 1).
Most of these series are old, and surgical techniques and supportive care have evolved. A Turkish series of 35 patients with MPM provides contemporary insight into the natural history of the disease, as most patients received palliative chemotherapy or supportive care only [8]. The mean age was 59 years and the overall survival time from diagnosis was 16 months. In multivariate analysis, patients who were over age 60, individuals who were exposed to asbestos for >20 years, and those who had an Eastern Cooperative Oncology Group performance status of 3 (table 2) at diagnosis were more likely to have a poor prognosis. Performance status at diagnosis was the strongest predictor of poor outcome.
Additional information is available from two retrospective reports comparing outcomes of patients treated with conventional therapies versus cytoreductive surgery (CRS)/hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) [9,10], described in the following section.
Evolution of modern therapy — The concept of aggressive surgical cytoreduction and intraperitoneal chemotherapy with hyperthermia for diffuse MPM was introduced in the mid 1990s [11]. Intraperitoneal chemotherapy used in the operating room with hyperthermia has many nomenclatures, including continuous hyperthermic peritoneal perfusion, heated intraoperative peritoneal chemotherapy, and HIPEC. The remainder of this topic review will use the term HIPEC. Some centers also extend the period of IP chemotherapy beyond the operating room, an approach termed early postoperative intraperitoneal chemotherapy (EPIC).
As experience with CRS and HIPEC has accumulated from several centers, particularly over the last 15 years, marked improvements in outcome have been reported compared with historical controls [12]. In contrast to conventional therapies, with which median survival was mostly ≤12 months, among centers with expertise in this form of therapy, reported median survival for appropriately selected patients is 34 to 100 months.
Although limited, the following comparative studies are available:
●In a series of 1514 patients with MPM reported to the National Cancer Database between 2004 and 2013, 379 underwent observation alone, 370 received chemotherapy only, 197 had surgical cytoreduction alone, 352 had CRS plus chemotherapy, and 216 underwent CRS/HIPEC [10]. In multivariate analysis, as compared with the CRS/HIPEC cohort, receipt of surgical cytoreduction alone, chemotherapy only, or observation were independently associated with inferior survival; in contrast, the group receiving surgical cytoreduction plus chemotherapy had a similar survival. The corresponding five-year overall survival rates for CRS/HIPEC, CRS/chemotherapy, CRS alone, chemotherapy alone, and observation were 52, 42, 22, 22, and 9 percent, respectively.
●A population-based Dutch study of 566 patients diagnosed with MPM between 1993 and 2016 found that compared with best supportive care alone, improved survival was independently associated with the use of surgery (hazard ratio [HR] 0.33, 95% CI 0.23-0.48), HIPEC (HR for death 0.33, 95% CI 0.21-0.55), and systemic chemotherapy (HR 0.61, 95% CI 0.49-0.76) [9]. Two-year survival rates were 50 percent with CRS/HIPEC, but they were not significantly different with surgery plus systemic chemotherapy (44 percent, HR for death 1.115, 95% CI 0.867-1.435). By contrast, outcomes were significantly better for CRS/HIPEC compared with CRS alone (22 percent, HR for death 1.859, 95% CI 1.378-2.509), chemotherapy alone (18 percent, HR for death 1.843, 95% CI 1.450-2.341), and best supportive care and other forms of therapy (8 percent, HR for death 2.903, 95% CI 2.270-3.702).
For patients who are not candidates for CRS/HIPEC due to unresectable disease or medical comorbidities, systemic chemotherapy with contemporary pemetrexed-based regimens achieves response rates comparable to those seen in patients with pleural mesothelioma and is now commonly incorporated into some peritoneal mesothelioma treatment algorithms (algorithm 1). There are a small number of reports of immune checkpoint inhibitor immunotherapy in peritoneal mesothelioma; although the bulk of the data are in malignant pleural mesothelioma, with some early phase clinical trials included peritoneal as well as pleural disease. (See 'Efficacy of systemic chemotherapy' below.)
Cytoreductive surgery and intraperitoneal chemotherapy — For selected patients with diffuse MPM, no extraperitoneal disease spread, a good performance status, and who can be predicted to achieve complete surgical cytoreduction based upon preoperative imaging, we recommend regional therapy using cytoreductive surgery (CRS) and HIPEC rather than systemic or intraperitoneal chemotherapy or surgical debulking alone. Outcomes are optimal when patients are referred to and treated in centers with expertise in the management of peritoneal surface malignancies. For patients who are not candidates for CRS/HIPEC, we suggest systemic chemotherapy rather than debulking surgery.
In the past, MPM was treated at most cancer centers with a combination of cytotoxic chemotherapy, palliative surgery, and in a few patients, total abdominal radiation, and median survival durations were uniformly approximately one year, and there were few, if any, five-year survivors [2,7,13-16]. (See 'General treatment principles and historic evolution' above.)
Although randomized trials have not been conducted, as the number of centers utilizing CRS/HIPEC has expanded, particularly over the last ten years, marked improvements in median survival for MPM ranging from 34 to 100 months have been reported in patients treated with CRS/HIPEC, with five-year survival rates from 29 to 59 percent [2,9,10,17-22]. Significant reductions in morbidity and mortality rates have also been achieved [23].
Results in contemporary series of patients treated with CRS/HIPEC are discussed in more detail below. (See 'Results' below.)
Rationale — Briefly, the rationale for CRS/HIPEC therapy in MPM is as follows:
●MPM remains confined to the peritoneal cavity in the majority of cases. Because peritoneal implants are often superficial and do not invade underlying tissues deeply until the late stages, the disease is amenable to complete or near complete cytoreduction in over one-half of all patients undergoing exploration. The completeness of surgical cytoreduction is a major prognostic factor. (See 'Patient selection' below.)
●Direct intraperitoneal administration of chemotherapy permits a several-fold increase in drug concentration in the peritoneum compared with systemic administration. Despite this regional advantage, direct penetration into tumor tissue is limited to a few millimeters. This may be enhanced by heating the perfusate containing chemotherapy, but even so, this form of therapy is best restricted to small volume disease.
Additional detailed information on rationale for HIPEC is presented elsewhere. (See "Anesthesia for cytoreductive surgery with heated intraperitoneal chemotherapy", section on 'Hyperthermic intraperitoneal chemotherapy'.)
Good results from CRS/HIPEC can be achieved with optimally selected patient populations and with treatment delivery in a center with expertise in these technically demanding procedures:
●This approach is best suited for patients with no evidence of extraperitoneal spread, a good performance status, and a disease burden that is amenable to cytoreduction to minimal residual disease (no deposits over 2 to 2.5 mm) [24]. It is unlikely that even a heated solution of chemotherapy could penetrate large tumor deposits.
●The favorable results (particularly in regard to treatment-related toxicity) achieved by international experts in the field may not be replicated in routine clinical practice. Patients with MPM should be managed at an institution with demonstrated experience in this therapy. The quality of the CRS is dependent upon the skills and level of experience of the surgeon [25]. Even at dedicated treatment centers, major morbidity is experienced by at least 30 percent of patients, the median hospital stay is 12 days, and the operative mortality rate is approximately 2 percent [26].
Guidance as to centers with expertise in treatment of peritoneal mesothelioma in the United States is available from the nonprofit Mesothelioma Applied Research Foundation (MARF).
Patient selection — Several factors are associated with better outcomes after CRS and HIPEC, some of which are useful for stratifying patients into groups that are more or less likely to benefit from this aggressive approach. These include disease extent and depth of tumor invasion beyond the mesothelial surface, the predicted completeness of cytoreduction, histology (epithelioid better than sarcomatoid or biphasic), age (less than 60 better than older), the presence of preoperative thrombocytosis, and weight loss [27-34]. Female gender may also be independently associated with a better prognosis, with younger women (<55 years of age) doing better than older women [35].
Results from the initial staging computed tomography (CT) scan can be used to predict the likelihood of complete surgical cytoreduction. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Radiographic imaging'.)
The Washington Hospital Center team systematically scored findings on preoperative CT scans from 30 patients undergoing CRS and HIPEC for MPM, and identified features associated with adequacy of cytoreduction [36]. The presence of a >5 cm mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery (matted adjacent small bowel loops, distorted and thickened configuration, segmental small bowel obstruction, small bowel mesenteric vessels difficult to define due to obliteration of mesenteric fat) were the radiographic features that were most strongly associated with suboptimal cytoreduction. Patients who had neither of these two findings had a 94 percent probability of adequate cytoreduction (defined as all residual tumor nodules <2.5 cm in diameter), while no patient with both findings had a successful surgical cytoreduction.
Others have identified unfavorable radiographic imaging findings, including large volume upper abdominal disease and disease that is visible in the small bowel as reducing the likelihood of complete surgical cytoreduction [37].
Radiographic criteria such as these are used to select patients with a peritoneal surface malignancy who are most likely to benefit from aggressive surgical debulking and HIPEC. Other factors are derived intraoperatively.
The Sugarbaker group uses four preoperative and intraoperative features to select patients for combined treatment [38,39]:
●Preoperative contrast (oral and IV)-enhanced CT of the chest, abdomen, and pelvis – In addition to excluding liver or other systemic metastases, the finding of segmental obstruction of the small bowel and tumor nodules >5 cm in diameter on small bowel surfaces or directly adjacent to the small bowel mesentery in the jejunum or upper ileum predict a poor outcome from CRS and HIPEC.
●Histopathology – Noninvasive malignancies such as mesothelioma are more likely to be made visibly disease-free through a peritonectomy procedure and are less likely that other invasive histologies (eg, colonic adenocarcinoma) to have spread to regional nodes, liver, or other systemic sites.
●Two other clinical indices, the peritoneal cancer index (PCI; a quantitative prognostic indicator derived from the size and distribution of peritoneal surface nodules), and the completeness of cytoreduction score (ie, size of persisting nodules after maximal cytoreduction) are derived intraoperatively [40,41].
Laparoscopy may also be used to predict which patients are likely to have a complete surgical cytoreduction during a subsequent laparotomy [42].
Technique — Intraoperative procedures that may be used to achieve complete gross cytoreduction include omentectomy, splenectomy, small and large bowel resection, peritonectomy, hysterectomy, salpingectomy, oophorectomy, and low anterior resection. Implants on the capsule of the liver or other solid viscera are usually treated by electrical or argon beam coagulation or some other type of electrofulguration.
HIPEC is done selectively and may be omitted if CRS has been suboptimal. The degree to which surgical cytoreduction versus intraperitoneal chemotherapy contributes to patient outcomes is unclear.
The treatment parameters for HIPEC (type of chemotherapy, degree of hyperthermia, and duration of perfusion) vary considerably from one institution to another. (See "Anesthesia for cytoreductive surgery with heated intraperitoneal chemotherapy", section on 'Infusion procedure'.)
Although many chemotherapy agents have been used for HIPEC (table 3), the most commonly used for peritoneal mesothelioma are mitomycin or cisplatin [43]. There are scant data to support any specific regimen over another:
●Two retrospective reports suggest that patients treated with intraperitoneal cisplatin via HIPEC may have superior survival compared with those treated with mitomycin [44,45].
●A study has reported outcomes that are similar to others in 19 patients with MPM (four had progressive benign multicystic mesothelioma) treated with CRS and HIPEC using oxaliplatin [46].
●A retrospective database series of 249 patients undergoing CRS and HIPEC for peritoneal mesothelioma concluded that there was no difference in outcomes for any of the single chemotherapy agents, but that overall survival was better with two drugs as compared with one [47].
Interpretation of all of these reports is limited by their retrospective nature. The bottom line is that there are no consistent data favoring one type of chemotherapy over another. A standard approach includes the following:
●After maximal surgical debulking, large bore catheters are placed within the peritoneal cavity and connected to an extracorporeal recirculating perfusion circuit consisting of a reservoir, roller pump, and heat exchanger.
●Four to 6 L of perfusate containing mitomycin at a dose of 40 mg or cisplatin 75 mg/m2 (based on ideal body weight) are circulated through the peritoneal cavity for 90 minutes. The perfusate is warmed to achieve target intraperitoneal temperatures between 40 and 42ºC.
●Some leave catheters in place for postoperative continuation of intraperitoneal chemotherapy, but most do not [27,48,49].
Additional information on the technical aspects of delivering intraoperative HIPEC is provided elsewhere. (See "Anesthesia for cytoreductive surgery with heated intraperitoneal chemotherapy", section on 'Infusion procedure'.)
Results — Over the past 30 years, there have been a large number of single center and two multicenter reports that detail the outcomes of patients treated with operative resection (CRS) and HIPEC or EPIC for MPM. The median overall survival ranges from 30 to 92 months, and this large range most likely reflects variations between centers with respect to patient selection criteria [12,18,27,50-52]. Despite the absence of randomized controlled trials demonstrating a benefit of CRS and HIPEC, this approach has been accepted as first-line treatment for selected MPM patients who have a good performance status and a disease burden that is amenable to complete (or near complete) cytoreduction. Multiple single institution studies have consistently shown favorable survival with this approach as compared with historical survival data from treatment with systemic chemotherapy alone or in conjunction with palliative surgery (figure 1). The overall median survival durations for patients treated with CRS and HIPEC were 53 and 38 months in two large multi-center studies [45,53].
●The largest multi-institutional registry combining retrospective data on patients with MPM treated with CRS and HIPEC at 29 clinical centers worldwide included 405 patients with MPM; a variety of intraperitoneal chemotherapeutic agents were utilized during HIPEC including cisplatin, mitomycin C, and doxorubicin [53]. The median actuarial overall survival was 53 months with one-, three-, and five-year survival rates of 81, 60, and 47 percent, respectively. Prognostic factors associated with improved survival on multivariate analysis were epithelioid histologic subtype, absence of lymph node metastases, complete or near complete resection (ie, completeness of cytoreduction score [CC] 0 or 1 (table 4)) [54], and the use of HIPEC.
●A second multi-institutional report that included 211 patients treated at three centers in the United States (which were not part of the previous study) showed an actuarial overall survival of 38 months and 5- and 10-year survival rates of 41 and 26 percent, respectively [45]. All patients underwent CRS and HIPEC using either cisplatin or mitomycin C. Prognostic factors associated with improved survival were age less than 60 years, complete or near complete gross resection (CC-0 or 1, (table 4)), low versus high histologic grade, and the use of cisplatin versus mitomycin C (figure 2). Although retrospective, the data suggested a better outcome of HIPEC using cisplatin in patients with this disease; interestingly, the benefit was most marked in those who had a CC-0 or 1, and there was no benefit to HIPEC with either agent in patients who had a suboptimal surgical cytoreduction (CC >2 (table 4)). This observation confirmed a prior series that showed a trend towards improved survival with cisplatin rather than mitomycin [44].
Results from these reports and several contemporary single center studies of CRS and HIPEC are outlined in the table (table 5) [19,45,53,55-58]. These results compare favorably with other, mostly older, reports detailing the efficacy of CRS/HIPEC and the factors that influence outcomes, including age under 60, incomplete surgical cytoreduction, sarcomatoid growth pattern, and degree of tissue invasion [27,29,32,59].
Over time, improvements in patient selection seems to have resulted in better outcomes from CRS/HIPEC. This was suggested in an analysis of 1591 patients diagnosed with MPM between 1973 and 2010 derived from the Surveillance, Epidemiology, and End Results database [60]. A number of parameters were associated with a greater risk of shortened survival, including advancing age, male gender, histology (biphasic or sarcomatoid versus epithelioid), and extent of disease. Surgical resection was associated with improved survival overall and survival after surgical resection improved over time. However, 57 percent of individuals diagnosed with MPM during the most recent time interval (2006 to 2010) did not undergo any time of surgical resection, suggesting that many individuals who may be good candidates for surgical resection are not presented with this option.
The benefits of CRS/HIPEC were confirmed in a systematic review of 20 publications totaling 1047 patients with MPM [18]. Complete or near complete surgical cytoreduction (CC-0 or CC-1 (table 4)) was achieved in 67 percent of patients, and the estimated five-year survival was 42 percent. Treatment factors associated with improved survival included the use of EPIC and the use of cisplatin alone or in combination during HIPEC or EPIC. Some of the publications included in the meta-analysis were sequential reports from one institution, which may have included overlapping cohorts of patients.
Several studies have shown that HIPEC can also palliate malignant ascites in patients with MPM, even in those who have suboptimal or no surgical cytoreduction [61,62].
Treatment of recurrent disease — For patients with recurrence after initial CRS/HIPEC, repeat CRS and HIPEC in selected patients can result in long-term survival, although patient selection is critical [63-65]. A study from the Washington Hospital Center reported the outcomes of 44 patients out of 205 with MPM who underwent a second CRS and HIPEC [63]. Median overall survival was 54 months in those undergoing a second CRS and HIPEC versus 77 months for those after initial CRS and HIPEC. Notably, the ability to achieve a complete or near complete (CC-0 or CC-1 (table 4)) resection was significantly lower in patients undergoing a second CRS and HIPEC.
In an updated report from the same center, the authors noted that patients with no or minimal symptoms and those with limited radiographic evidence of recurrent disease had longer survival than those with abdominal pain or distention or those who had radiographic evidence of solid tumor masses in the abdomen [66]. These and other data [64] highlight the need for careful patient selection.
Treatment-related toxicity — In general, with improvements in patient selection, operative technique, and postoperative management, the mortality associated with CRS and HIPEC has decreased, and overall survival has increased over the past 25 years. In expert hands, CRS and HIPEC treatment is associated with an operative mortality rate that ranges from 0 to 8 percent, and rates of serious perioperative morbidity are between 10 and 45 percent. Complications related to chemotherapy are almost invariably related to myelosuppression, while complications related to laparotomy and CRS include fistula, bleeding, wound infection, and sepsis.
The range of findings can be illustrated by the following reports:
●Passot et al have reported a 25-year institutional experience with CRS and HIPEC in 1125 patients with a variety of peritoneal malignancies (84 [8 percent] with MPM) [12]. There were some significant trends over the last 10 years of the experience (which included almost 900 patients), such as selection of patients with a lower PCI, an increased proportion of patients undergoing a complete or near complete clinical response, and improved survival. Of note, while operative time and overall complication rates did not change, the operative mortality decreased significantly from 5 to 2 percent over time. These data reflect a general improvement in patient selection and, perhaps, an improvement in perioperative management that has translated into generally better outcomes. Complications were most commonly intra-abdominal events (abscess or fistula), observed in 20 percent of patients, followed by cardiovascular and respiratory events, each occurring in approximately 15 percent of patients.
●In a report from the Sugarbaker group, treatment-related toxicity was categorized as grade 1, no intervention reported for resolution; grade 2, medical treatment sufficient for resolution; grade 3, invasive (eg, radiologic or transfusional) intervention required for resolution; grade 4, urgent definitive intervention (eg, return to the operating room or to the surgical intensive care unit) required for resolution [48]. Grade 3 or 4 morbidity rates were 27 and 14 percent, respectively. Low hemoglobin level was responsible for 26 percent of all grade 3 toxicities, while central line sepsis and urinary tract infection accounted for 17 and 13 percent, respectively. Postoperative bleeding requiring a return to the operating room accounted for 38 percent of the grade 4 adverse events, and respiratory failure requiring intubation was responsible for 22 percent. Risk factors for grade 4 morbidity included primary colonic anastomosis, more than four peritonectomy procedures, and operative duration over seven hours.
●Long-term consequences seem to be limited; however, in a series of 42 patients (two with MPM) undergoing CRS and HIPEC at a high-volume center in Toronto, Hamilton et al reported a 33 percent major complication rate, which was associated with a significantly longer average length of hospital stay compared with those without complications (35 versus 13 days, respectively) [67]. Despite this, the authors noted no differences in any measured quality of life parameter between the groups at six months after treatment, suggesting that there are limited long-term consequences to perioperative morbidity after CRS and HIPEC. This observation has been reported by others [68].
These data are derived from groups with demonstrated experience and expertise in the procedure, and they may not be replicated in routine clinical practice. However, analysis of a large group of experienced centers through the American College of Surgeons National Surgical Quality Improvement Project (NSQIP) reveals that CRS/HIPEC is not associated with higher complication rates than other surgical procedures. A study of the NSQIP database demonstrates overall 30-day mortality was lower in CRS/HIPEC compared with Whipple, right lobe hepatectomy, esophagectomy, and trisegmental hepatectomy [23]. Guidance as to centers with expertise in treatment of peritoneal mesothelioma is available from the nonprofit Mesothelioma Applied Research Foundation (MARF).
Contribution of systemic therapy — The role of systemic chemotherapy in conjunction with CRS plus HIPEC is uncertain, and there is no consensus on when or if it should be used; these decisions must be individualized. For patients in whom the timing of operative CRS and HIPEC must be delayed, we suggest a course of initial systemic chemotherapy until the definitive operation can be performed. Others suggest the use of initial systemic chemotherapy for all biphasic/sarcomatoid histologies and for epithelioid histology cases in which incomplete cytoreduction is predicted, with CRS/HIPEC offered to those who subsequently convert to a radiographic assessment of "complete cytoreduction predicted" (algorithm 1) [69]. (See 'Patient selection' above.)
If upfront chemotherapy is chosen, we suggest a pemetrexed plus platinum-containing regimen, similar to that used for nonresectable disease. Notably, bevacizumab should not be used in the neoadjuvant setting due to the high likelihood of poor wound healing, concerns about intra-abdominal bleeding or perforation, and the long half-life of that agent. (See 'Efficacy of systemic chemotherapy' below.)
After CRS and HIPEC, we suggest systemic chemotherapy as consolidation treatment if high-risk histopathologic features are present, such as the presence of deep tissue invasion, biphasic histology, or baseline thrombocytosis. For patients with optimal cytoreduction and no histopathologic features that would suggest increased risk of early recurrence, no systemic therapy is recommended.
The utility of adjuvant or neoadjuvant systemic chemotherapy has not been formally addressed in prospective clinical trials. The following data are available from retrospective analyses:
●Using the United States National Cancer Database, investigators compared outcomes between those patients receiving chemotherapy only, surgery only, or surgery with adjuvant or neoadjuvant therapy [70]. Surgery was rigorously defined as debulking or radical surgery with a report of complete cytoreduction. Of 1136 patients, 55 (3.2 percent) had neoadjuvant chemotherapy prior to complete cytoreduction, 228 (13.1 percent) had adjuvant chemotherapy following complete cytoreduction, and 684 (39.3 percent) patients had surgery alone. Long-term outcomes were similar among all three groups, with patients receiving any chemotherapy appearing to do better, at least in the first year. However, it is plausible that patients with complete cytoreduction who did not receive additional therapy had either comorbidities or surgical morbidities that may have affected their ability to receive perioperative chemotherapy.
●Investigators at the National Cancer Institute of Milan reported outcomes in 116 MPM patients, some of whom received neoadjuvant and/or adjuvant systemic chemotherapy in addition to HIPEC [71]. Although the criteria used to select patients for perioperative chemotherapy were not well defined, there was no association between use of chemotherapy and completeness of cytoreduction, operative morbidity, or survival in the cohort of 60 patients who received neoadjuvant chemotherapy; there was no hint of a survival benefit from the use of postoperative chemotherapy.
●Similarly, a retrospective review of 126 patients with diffuse MPM treated at one of 20 French centers from 1991 to 2014 with CRS plus HIPEC included cohorts treated with neoadjuvant (n = 42), adjuvant (n = 16), perioperative (n = 16), or no chemotherapy (n = 48); as with the Milan series, the criteria used to select patients for a specific approach were not specified [72]. Contemporary pemetrexed-based regimens were administered in only 62 percent of patients. There was no significant difference in survival between patients receiving no chemotherapy and those receiving either adjuvant alone or perioperative chemotherapy (five-year overall survival 56, 67, and 62 percent, respectively), while patients receiving neoadjuvant therapy had a lower five-year survival rate (40 percent). On multivariate analysis, the sole factor independently associated with better overall survival was the lack of neoadjuvant therapy (HR 2.2, p = 0.033). Adjuvant chemotherapy (p = 0.006) and treatment period after 2005 (p = 0.030; after the approval of pemetrexed) were associated with an improved progression-free survival on univariate, but not multivariate, analysis.
Given the limited sample size and retrospective nature of this series, these data should be interpreted cautiously. The authors speculated that neoadjuvant chemotherapy may have been offered more frequently to those patients with more aggressive disease, while patients who had a good response to neoadjuvant treatment may have been more likely to later receive adjuvant chemotherapy and were, thus, included in the perioperative, rather than the neoadjuvant, group. Alternatively, these data may suggest a lower sensitivity to chemotherapy in unresected patients with bulkier disease. The authors also concluded that the longer progression-free survival in patients who received adjuvant chemotherapy, especially contemporary regimens, suggests that this should be considered to delay recurrence and potentially improve survival.
Approach to patients who are not candidates for CRS/HIPEC — For patients who are not candidates for cytoreductive surgery (CRS)/hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC), we suggest systemic chemotherapy rather than debulking surgery. For most patients, we suggest a pemetrexed-containing regimen over other chemotherapy options. Pemetrexed plus cisplatin (table 6) is an active regimen if the patient's performance status and general health are adequate to tolerate it. Particularly in the palliative setting, pemetrexed plus carboplatin (table 7) might be preferred given that it achieves similar results with less toxicity. Another option for first-line treatment, for patients who can tolerate it, is the addition of bevacizumab to pemetrexed plus a platinum agent. When the chemotherapy regimen includes pemetrexed, concurrent supplementation with vitamin B12 and folic acid is needed to reduce toxicity. (See 'Pemetrexed-based regimens' below and "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed plus cisplatin'.)
Efficacy of systemic chemotherapy
Peritoneal versus pleural mesothelioma — Trials that have been conducted exclusively in patients with peritoneal mesothelioma are quite uncommon, and assumptions about the activity of various chemotherapeutic agents for peritoneal mesothelioma are often extrapolated from the more extensive data derived from patients with pleural mesothelioma. It is generally assumed (and supported by uncontrolled data [73]) that the efficacy of most systemic chemotherapy is similar in both disease sites, despite variations in gene expression profiles that suggest different pathophysiology for pleural and peritoneal mesothelioma.
Most clinical trials that evaluate new drugs or drug combinations in mesothelioma specifically exclude patients with peritoneal mesothelioma. Those trials that do permit the enrollment of mesothelioma disease sites other than the pleura generally include few peritoneal mesothelioma subjects due to the rarity of peritoneal mesothelioma and the standard eligibility requirement for radiologically measurable disease, which can be difficult to determine in the peritoneal cavity. Furthermore, trials may not report results in patients with peritoneal mesothelioma separately due to the small numbers.
Prospective trials, such as Alliance A092001, a randomized trial of pemetrexed plus carboplatin and bevacizumab, with or without atezolizumab, should enhance our understanding of the activity of both chemotherapy and immunotherapy at this disease site.
Choice of regimen — A meta-analysis of clinical trials reported between 1965 and 2001 determined that cisplatin was the single most active cytotoxic agent against mesothelioma [74]. Single-agent cisplatin was used as the control arm of two large phase III trials in pleural mesothelioma [75,76], although in clinical practice, it is never administered as monotherapy outside of a clinical trial setting. The addition of cisplatin to other active single agents, such as pemetrexed, raltitrexed, gemcitabine, or vinorelbine, increases the objective response rate [77]. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Subsequent-line treatment'.)
The antifolates are currently considered the most active class of drugs against mesothelioma. Pemetrexed, an antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase, is the first and only drug approved in the United States for the treatment of mesothelioma. Approval was based upon a single-blind, placebo-controlled, randomized phase III study in which 456 patients with pleural mesothelioma were randomly assigned to pemetrexed, 500 mg/m2 every 21 days plus cisplatin, 75 mg/m2, or placebo with cisplatin. Those patients who received pemetrexed plus cisplatin achieved a significantly superior overall survival (12.1 versus 9.3 months, respectively; p = 0.020), longer time to disease progression (5.7 versus 3.9 months, p = 0.001), and higher objective response rate (41 versus 17 percent) [75]. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed plus cisplatin'.)
The following discussion will focus on data obtained in patients with MPM. General principles of systemic therapy for pleural and other forms of mesothelioma are discussed elsewhere. (See "Systemic treatment for unresectable malignant pleural mesothelioma".)
Pemetrexed-based regimens — The utility of pemetrexed in patients with MPM has principally been demonstrated in analyses of the Pemetrexed Expanded Access Program, both in the United States and internationally [78,79]. Prospective phase II or III clinical trials of this regimen have not been conducted in patients with peritoneal mesothelioma, however.
●Pemetrexed plus cisplatin – Systemic chemotherapy with pemetrexed plus cisplatin has been a cornerstone of treatment for advanced pleural mesothelioma since 2004 when the EMPHACIS trial demonstrated better outcomes for this combination compared with cisplatin alone. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed plus cisplatin'.)
The available data suggest that the efficacy of pemetrexed plus cisplatin is comparable in peritoneal mesothelioma to that seen in malignant pleural mesothelioma, and the regimen has generally been well tolerated. Of the 1056 mesothelioma patients enrolled in the United States Expanded Access Program prior to US Food and Drug Administration (FDA) approval of pemetrexed, 98 (9.3 percent) had peritoneal primary sites. Fifty-seven were previously treated, and 38 were chemotherapy-naive. Patients received either pemetrexed alone (500 mg/m2 every 21 days, n = 32) or the same dose of pemetrexed in combination with cisplatin (75 mg/m2 every 21 days, n = 66) for six cycles or until disease progression (table 6) [78]. Folic acid (350 to 600 mcg daily) and vitamin B12 (1000 mcg intramuscularly one to two weeks before the first dose, then every nine weeks) were administered to all patients. Vitamin supplementation improves response to therapy and reduces treatment-related toxicity.
Since measurable disease was not required for enrollment, only 73 patients with MPM were evaluable for response (28 chemotherapy-naive and 43 previously treated). Twenty-six received single-agent pemetrexed and 47 were given the two-drug combination. There were 19 objective responses (four complete) for an overall response rate of 26 percent; another 45 percent had stable disease. The disease control rate (objective responses plus stable disease) was 71 percent, and similar objective response rates were achieved in the previously-treated and chemotherapy-naive patients. Median overall survival for previously-treated patients was 13.1 months; it had not been reached at the time of the analysis for chemotherapy-naive patients. As expected, both response rate (29 versus 19 percent) and median survival (13.1 versus 8.7 months) were higher with the pemetrexed doublet than with pemetrexed alone (although the survival outcomes could easily reflect patient selection in this nonrandomized study), and in both cases, the results were comparable with those seen in pleural mesothelioma. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed plus cisplatin'.)
Treatment appeared to be well tolerated. The safety database of 1056 patients did not distinguish between patients with pleural or peritoneal mesothelioma, so it is uncertain whether there were any distinct toxicities in the peritoneal subset. The safety analysis in this trial relied on investigator reported serious adverse events, and thus the true rate of toxicity derived from analysis of experience in the Expanded Access Program is likely much greater than reported. Grade 3 or 4 hematologic toxicity (primarily anemia) was documented in only 2 percent of patients and neutropenia, in less than 1 percent. The most common grade 3 or 4 nonhematologic toxicities were dehydration (7 percent), nausea (5 percent), and vomiting (5 percent).
●Pemetrexed plus carboplatin – Carboplatin is often substituted for cisplatin, particularly in the palliative setting and in older patients [77]. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Pemetrexed plus carboplatin'.)
In the International Pemetrexed Expanded Access Program, 29 evaluable patients with peritoneal mesothelioma received pemetrexed 500 mg/m2 and carboplatin, dosed at an area under the concentration X time curve of 5 mg/mL x min, supplemented with standard vitamin B12, folate, and dexamethasone (table 7) [79]. Seven patients (24 percent) had objective responses (one complete), and 52 percent had stable disease. These results are comparable to those achieved with pemetrexed and cisplatin.
●Pemetrexed plus cisplatin and bevacizumab – The addition of bevacizumab to the pemetrexed-cisplatin regimen improved both progression-free and overall survival compared with pemetrexed plus cisplatin without bevacizumab in the large phase III MAPS trial conducted exclusively in patients with malignant pleural mesothelioma [80]. It is reasonable to extrapolate this experience to patients with MPM, although care should be taken in patient selection for bevacizumab (patients should have no poorly controlled hypertension, deep venous thrombosis, recent or planned surgery, or viscus perforation, and they must have a good performance status). This trial is discussed in more detail elsewhere. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Addition of bevacizumab'.)
●Pemetrexed plus gemcitabine – One of the largest prospective multicenter chemotherapy experiences reported in peritoneal mesothelioma evaluated the combination of gemcitabine (1250 mg/m2 on days 1 and 8) plus pemetrexed (500 mg/m2 on day 8, before gemcitabine) in 20 chemotherapy-naive but highly selected patients with peritoneal mesothelioma [81]. A median of six cycles were delivered. There were three partial responses (response rate 15 percent), and 35 percent had stable disease, for a disease control rate of 50 percent. Median time to disease progression was 10.4 months, median overall survival was 26.8 months, and one-year survival was 67.5 percent. However, hematologic toxicity was substantial, and included grade 3 or 4 neutropenia in 60 percent, febrile neutropenia in 10 percent, and grade 4 anemia in 5 percent. The most common grade 3 and 4 nonhematologic toxicities included fatigue in 20 percent, and constipation, vomiting, and dehydration, each in 10 percent of patients.
Importantly, this phase II trial was conducted in patients with predominantly pleural mesothelioma, and this report covered the 20 patients with peritoneal mesothelioma who were allowed to enroll, but without a statistical plan for separate analysis. As such, the data should be considered the equivalent of an observational study. We do not consider this a valid regimen for peritoneal mesothelioma given its toxicity and the low response rate (15 percent), which is comparable with that which can be achieved using pemetrexed alone, and lower than would be expected with pemetrexed plus cisplatin or carboplatin.
Cisplatin plus irinotecan — Responses have also been described with cisplatin administered intraperitoneally or IV, in combination with IV irinotecan in a retrospective single-institution series [82].
Other regimens — Gemcitabine plus cisplatin or carboplatin is an active regimen in pleural mesothelioma, but data are not available in patients with a peritoneal primary site [77]. Similarly, vinorelbine has a 24 percent single agent response rate in the front-line setting [83] and a 16 percent response rate in previously-treated pleural mesothelioma patients [84]. Whether these data are applicable to peritoneal patients is unclear, but the drugs are often used.
Molecularly targeted therapy — Preclinical data suggest a possible role for phosphatidylinositol-3-kinase (P13k) and inhibitors of the mechanistic (previously called mammalian) target of rapamycin signaling pathway in the malignant phenotype of diffuse MPM [85]; phase I and II trials of agents that target these pathways are ongoing.
Data on novel molecular pathways in mesothelioma (eg, rearrangements in the anaplastic lymphoma kinase gene [86]) are emerging, and they may have implications for future therapy using agents that target these abnormalities. Data on agents that target novel molecular pathways in mesothelioma, including mesothelin and vascular endothelial growth factor pathways, as well as inhibitors of histone deacetylase and focal adhesion kinase, are discussed elsewhere. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Investigational therapies'.)
Immunotherapy — Immune checkpoint inhibitors, immunomodulatory antibodies that are used to enhance the antitumor activity of the immune system are now in routine use in multiple solid tumor types, including pleural mesothelioma. (See "Principles of cancer immunotherapy".)
The role of immunotherapy in peritoneal mesothelioma is evolving, but given its approval for pleural mesothelioma, many clinicians are using it for peritoneal primaries, despite persisting questions as to whether data in pleural mesothelioma can always be extrapolated to the peritoneal disease site.
●Pleural mesothelioma – It is clear that immune checkpoint inhibitors that target the programmed cell death protein 1 (PD-1) receptor alone or in combination with agents that inhibit a second immune checkpoint, cytotoxic T-lymphocyte antigen-4 (CTLA-4), have activity in pleural mesothelioma (see "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Immunotherapy'). Briefly:
•Single-agent pembrolizumab and nivolumab, both inhibitors of the PD-1 pathway, are both active agents in advanced pretreated disease.
•The MAPS2 trial demonstrated a benefit for nivolumab plus the CTLA-4 inhibitor ipilimumab over nivolumab alone for second- or third-line therapy of advanced pretreated pleural mesothelioma [87]. None of the patients on this trial had a peritoneal primary site.
On the other hand, a progression-free and overall survival benefit for nivolumab alone versus placebo in patients previously treated with a first-line platinum-based chemotherapy regimen was shown in the CONFIRM trial [88]. In the CONFIRM trial, 5 percent of the enrollees (16 of 332) had an extrapleural site, but outcomes were not stratified according to primary site.
•Efficacy was also shown for combined nivolumab plus ipilimumab in treatment-naive patients in the CheckMate 743 trial, although the survival benefit appeared to be limited to those with nonepithelioid (ie, biphasic, sarcomatoid) histology [89], Largely based on these results, the combination of nivolumab plus ipilimumab was approved by the FDA for unresectable pleural mesothelioma in October 2020 [90,91], and the National Comprehensive Cancer Network (NCCN) considers this the preferred initial option for patients with nonepithelioid (ie, biphasic, sarcomatoid) tumors. None of the patients enrolled on this trial had a peritoneal primary site.
An important point is that not all patient subgroups benefit equally from immunotherapy. In pleural mesothelioma, the benefit for first-line immunotherapy seems strongest in patients with nonepithelial tumors, while the majority of peritoneal mesotheliomas are epithelial. The role of PD-L1 expression or other biomarkers in selecting appropriate candidates for immune checkpoint inhibitor immunotherapy is incompletely understood. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Nonepithelioid histology'.)
●Peritoneal mesothelioma – Given the relative lack of data in patients with a peritoneal primary, and concerns about benefit being limited to those with nonepithelioid histology in pleural mesothelioma, in our view, the available data are insufficient to conclude that immunotherapy using a checkpoint inhibitor alone or in combination (ie, ipilimumab plus nivolumab) is clearly superior to chemotherapy for first-line therapy for peritoneal mesothelioma patients; however, it may be a reasonable option for second-line therapy and beyond. There are no consensus-based guidelines from the NCCN or elsewhere that cover immunotherapy for peritoneal mesothelioma.
Only limited data on the efficacy of immune checkpoint inhibitor immunotherapy are available from small numbers of patients with peritoneal mesothelioma:
•Tremelimumab, a monoclonal antibody that targets CTLA-4, was evaluated in a 571-patient, double-blind, placebo-controlled, randomized phase IIb trial (DETERMINE) in patients with previously treated pleural or peritoneal (n = 26) mesothelioma. Unfortunately, there was no statistically significant difference in overall survival between the tremelimumab and placebo groups (HR 0.92, p = 0.41), and too few events to evaluate outcomes in the peritoneal subgroup separately [92].
•PD-1 and its ligand (PD-L1) may be more appropriate targets than CTLA-4 in peritoneal mesothelioma, although definitive conclusions are limited by the small numbers of treated patients in both preclinical and clinical series. A few small clinical trials to date have evaluated PD-1 and PD-L1 inhibitors in patients with peritoneal mesothelioma:
-In the phase Ib JAVELIN trial, 53 patients with pleural or peritoneal mesothelioma who had progressed after platinum and pemetrexed treatment (including 20 patients who had received three or more lines of therapy) were treated with avelumab, a monoclonal antibody that targets PD-L1 [93]. Five patients had a confirmed objective response (9 percent), and responses were durable (median 15.2 months). Using a PD-L1 expression cutoff of 5 percent or greater to define PD-L1-positive tumors, the investigators observed a higher response rate in PD-L1-positive tumors (3 of 16 [19 percent]) than in PD-L1-negative tumors (2 of 27 [7 percent]). Unfortunately, no conclusions can be drawn about the activity of avelumab in the peritoneal mesothelioma subset, as the number of peritoneal patients was not reported, and PD-L1 expression and treatment outcomes were not analyzed by disease site.
-A phase II trial evaluated the monoclonal antibody pembrolizumab, which targets PD-1, in 64 previously treated mesothelioma patients, including eight with peritoneal mesothelioma. All patients had received no more than two prior lines of cytotoxic chemotherapy, which must have included pemetrexed and a platinum. Although the response rate was greater in the pleural than in the peritoneal patients (20 versus 13 percent, respectively), PD-L1 expression was more common in the peritoneal subset. Only 25 percent of peritoneal patients were PD-L1 negative (defined as less than 1 percent expression), 50 percent were PD-L1 low (defined as 1 to 49 percent expression), and 25 percent were PD-L1 high (greater than or equal to 50 percent expression) [94,95].
-The NIBIT-MESO-1 trial included patients with either pleural or peritoneal mesothelioma, including both pretreated and treatment-naïve patients. Only two (5 percent) patients with peritoneal mesothelioma were enrolled, receiving combination tremelimumab and durvalumab; the combination appeared active, however, results were not reported separately from pleural disease [96]. (See "Systemic treatment for unresectable malignant pleural mesothelioma", section on 'Immunotherapy'.)
-Potential benefit for the combination of atezolizumab, a humanized monoclonal antibody that binds to PD-L1, plus bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF), was suggested in a phase II trial of 20 patients with advanced peritoneal mesothelioma and progression or intolerance to prior platinum-pemetrexed chemotherapy [97]. The confirmed objective response rate (primary endpoint) was 40 percent (8 of 20 patients), and median response duration was 12.8 months. At one year, 61 percent remained progression-free. Responses were independent of PD-L1 overexpression, or presence of deficient mismatch repair. Grade 3 or worse toxicities included hypertension in eight (40 percent) patients, anemia in two, and thrombocytopenia, pancreatitis, ileus, abdominal pain, thromboembolic event, and transaminase elevation in one each.
In our view, these data are too preliminary to support any specific recommendation for use of the combination in patients with peritoneal mesothelioma. Safety issues are a major concern. This group is potentially at risk for bowel perforation/anastomotic healing issues (which are seen at higher rates with bevacizumab) and the data set of 20 patients is too small to completely assess either safety or efficacy. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Intestinal perforation/fistula formation'.)
•Predictive biomarkers – It's also not clear whether there is any role for archival tumor expression of PD-L1 to identify subsets of patients with peritoneal mesothelioma who might respond to agents targeting PD-1. The proportion of tissue microarray samples positive for PD-L1 expression (defined as >1 percent tumor staining) using two FDA-approved immunohistochemistry markers was significantly higher in peritoneal (54 percent) than in pleural mesothelioma (18 to 22 percent) in one study, although only 13 peritoneal samples were evaluated [98]. Furthermore, others have demonstrated heterogeneity in PD-L1 expression that may be related to prior exposure to cytotoxic chemotherapy [99].
A very small number (approximately 2 percent) of mesotheliomas have high levels of microsatellite instability (MSI-H; also referred to as deficient in mismatch repair [dMMR]) [100], which may predict benefit from inhibitors that target PD-1 or PD-L1. (See "Principles of cancer immunotherapy", section on 'PD-1 and PD ligand 1/2'.)
In May 2017, the FDA approved pembrolizumab, a PD-1 inhibitor, for treatment of a variety of advanced solid tumors (including mesothelioma) that are MSI-H or dMMR, that progressed following prior treatment, and for which there are no satisfactory alternative treatment options. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
An important point is that MSI-H may indicate the presence of Lynch syndrome, an inherited condition that predisposes to several cancers, including possibly peritoneal mesothelioma [101,102]. In our view, all patients with peritoneal mesothelioma should be referred for germline testing given the high frequency of mutations in inherited cancer susceptibility genes in this disease (25 percent in one study [103,104]). (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Other factors' and "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Microsatellite instability testing'.)
PERITONEAL MESOTHELIOMA VARIANTS — There are two rare variants of peritoneal mesothelioma. Both are characterized by indolent behavior and the potential for malignant transformation to MPM. Although controversial (algorithm 1), we suggest initial surgical resection alone rather than cytoreductive surgery (CRS) and hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) for patients with the indolent well-differentiated peritoneal mesothelioma and multicystic mesothelioma variants. Long-term follow-up is warranted.
Well-differentiated papillary mesothelioma — Well-differentiated papillary mesothelioma is a rare clinicopathologic entity that is distinct from MPM. It occurs predominantly in women of reproductive age and most often arises from the peritoneal surfaces of the pelvis. It is typically identified as an incidental finding at surgery performed for another indication, and there is no reported association with asbestos exposure. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Well-differentiated papillary mesothelioma'.)
Well-differentiated papillary mesothelioma is generally considered a low-grade malignancy, with a high rate of cure following complete surgical resection [105,106]. Long-term follow-up is required because of the potential to progress to true MPM [106,107]. Extensive CRS and HIPEC are not warranted initially because in most patients there is no clearcut evidence of progression with follow-up. In a series of 25 patients followed for a median of 47 months, 22 had no evidence of disease progression and no patient died of disease [108]. Only one recurrence was described, and this was incidentally found at the time of abdominal surgery for a colon cancer; three died of other causes.
A variant of well-differentiated papillary mesothelioma with invasive foci has been identified. Though rarely life threatening, it can be multifocal and is slightly more aggressive, with a greater propensity to recur [109].
Multicystic mesothelioma — Multicystic mesothelioma (also termed benign cystic mesothelioma, peritoneal inclusion cyst) is an unusual cystic tumor that most commonly arises from the pelvic peritoneal surfaces in young and middle-aged women. Men represent only 17 percent of cases. The majority of cases present with chronic or intermittent lower abdominal or pelvic pain, but occasionally, the diagnosis is made incidentally at surgery or on cross-sectional imaging. There is no association with asbestos exposure. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Multicystic mesothelioma'.)
Although the disease is well characterized histologically, the pathogenesis (in particular whether it represents a reactive mesothelial proliferation or a true neoplasm), natural history, and clinical management are not well defined. The clinical course is usually indolent, and surgical resection can be curative. However, long-term follow-up is needed, since local recurrence can occur in up to 50 percent from 1 to 27 years after initial diagnosis [110,111], and malignant transformation is reported, although rare.
Surgical cytoreduction and HIPEC has been associated with long-term progression-free survival [112,113] and may be best applied when there is evidence of progression after initial resection.
Proposed nonsurgical forms of therapy include observation for asymptomatic patients with an incidentally discovered lesion, hormonal therapy [114,115], image-guided sclerotherapy [116], and laser ablation [117]. However, experience with any of these is largely limited to single case reports with limited follow-up, and whether any of these alternative approaches provides long-term control or eliminates the risk of malignant transformation is not known. In addition, if definitive surgery is not pursued, a tissue sample is required for histologic diagnosis [110,111].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Peritoneal mesothelioma".)
SUMMARY AND RECOMMENDATIONS
●Clinical features
•Malignant peritoneal mesothelioma (MPM) is an aggressive neoplasm that arises from the lining mesothelial cells of the peritoneum. As with mesothelioma arising in other sites, there is a strong relationship between asbestos exposure and the development of MPM, particularly in men. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Epidemiology and risk factors'.)
•The majority present with diffuse peritoneal involvement (diffuse MPM), and morbidity and mortality are almost entirely due to disease progression within the peritoneum and not distant metastatic spread. (See "Malignant peritoneal mesothelioma: Epidemiology, risk factors, clinical presentation, diagnosis, and staging", section on 'Clinical presentation and imaging features'.)
●Treatment
•Candidates for cytoreductive surgery
-For selected otherwise healthy patients with diffuse MPM, no extraperitoneal disease spread, a good performance status, and who can be predicted to achieve complete surgical cytoreduction based on initial radiographic imaging we recommend regional therapy using cytoreductive surgery (CRS) and hyperthermic intraoperative peritoneal perfusion with chemotherapy (HIPEC) rather than systemic or intraperitoneal chemotherapy or debulking surgery alone (Grade 2C). (See 'Cytoreductive surgery and intraperitoneal chemotherapy' above.)
Potential candidates for CRS/HIPEC should be referred to and treated in a center with expertise in the management of peritoneal surface malignancies. Additional factors including those derived intraoperatively, are used to select the optimal candidates for combined treatment. (See 'Patient selection' above.)
-The role of adjuvant or neoadjuvant systemic chemotherapy in conjunction with CRS plus HIPEC is uncertain, and there is no consensus as to the best approach. For patients in whom the timing of operative CRS and HIPEC must be delayed, we suggest a course of systemic chemotherapy until the definitive operation can be performed (Grade 2C). If upfront chemotherapy is chosen, we prefer a pemetrexed plus platinum-containing regimen, similar to that used for nonresectable disease. (See 'Contribution of systemic therapy' above.)
-Following CRS/HIPEC, for those patients whose tumors display high-risk features (eg, the presence of deep tissue invasion, biphasic histology, baseline thrombocytosis), we suggest a course of systemic chemotherapy as consolidation (Grade 2C). For patients with optimal cytoreduction and no histopathologic features that would suggest increased risk of early recurrence, we would not pursue systemic therapy.
•Not candidates for cytoreductive surgery
-For patients who are not candidates for CRS/HIPEC, we suggest systemic chemotherapy rather than debulking surgery with or without chemotherapy (Grade 2C).
For most patients, we suggest a pemetrexed-containing regimen over other chemotherapy options (Grade 2C). Options include pemetrexed plus cisplatin (table 6) or pemetrexed plus carboplatin (table 7) or bevacizumab in addition to pemetrexed plus a platinum agent. (See 'Pemetrexed-based regimens' above.)
When the chemotherapy regimen includes pemetrexed, concurrent supplementation with vitamin B12 and folic acid is needed to reduce toxicity.
-The role of immunotherapy is evolving. In our view, the available data are insufficient to conclude that immunotherapy using a checkpoint inhibitor alone or in combination (ie, ipilimumab plus nivolumab) should be considered as a first-line treatment option for MPM. However, checkpoint inhibitor immunotherapy may be a reasonable option for second-line therapy and beyond. There are no consensus-based guidelines from the National Comprehensive Cancer Network or elsewhere that cover peritoneal mesothelioma. (See 'Immunotherapy' above.)
-All patients with peritoneal mesothelioma should be referred for germline testing given the high frequency of mutations in inherited cancer susceptibility genes in this disease; testing may reveal deficiency in mismatch repair (dMMR), which might predict benefit from pembrolizumab. (See 'Immunotherapy' above.)
•Treatment of rare variants
-Although controversial (algorithm 1), for patients with the indolent well-differentiated peritoneal mesothelioma and multicystic mesothelioma variants we suggest initial surgical resection alone rather than CRS and HIPEC (Grade 2C).
-Long-term follow-up is warranted in these cases because of their indolent behavior. (See 'Peritoneal mesothelioma variants' above.)
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